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https://repository.monashhealth.org/monashhealthjspui/handle/1/58039| Title: | Cancer cell-intrinsic inflammasome protein ASC links innate immunity with mitochondrial metabolism in driving pancreatic cancer. | Authors: | Chey Y.C.J.;Kashgari B.;McLeod L.;Radford G.A.;Gearing L.J.;Dawson R.E.;Kharbanda M.;Lundy J.;Croagh D. ;Girard-Guyonvarc'h C.;Gabay C.;Pereira B.A.;Herrmann D.;Timpson P.;Finnie J.W.;Saad M.I.;Bhuva D.D.;Franklin B.S.;Schmidt F.I.;Jenkins B.J. | Monash Health Department(s): | Hudson Institute - Centre for Innate Immunity and Infectious Diseases Monash University - School of Clinical Sciences at Monash Health |
Institution: | (Chey, Radford, Dawson, Kharbanda, Saad, Bhuva, Jenkins) South Australian ImmunoGENomics Cancer Institute (SAiGENCI), The University of Adelaide, Adelaide, SA, Australia (Kashgari, McLeod, Gearing, Lundy, Jenkins) Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, VIC, Australia (Kashgari, McLeod, Gearing, Lundy, Jenkins) Department of Molecular Translational Science, School of Clinical Sciences, Monash University, Clayton, VIC, Australia (Lundy, Croagh) Department of Surgery (School of Clinical Sciences at Monash Health), Monash University, Clayton, VIC, Australia (Lundy) Peninsula Clinical School, School of Translational Medicine, Monash University, Frankston, VIC, Australia (Girard-Guyonvarc'h, Gabay) Division of Rheumatology, University Hospital of Geneva, Geneva, Switzerland (Girard-Guyonvarc'h, Gabay) Department of Pathology and Immunology, University of Geneva School of Medicine, Geneva, Switzerland (Pereira, Herrmann, Timpson) Cancer Ecosystems Program, Garvan Institute of Medical Research and The Kinghorn Cancer Centre, Darlinghurst, Sydney, NSW, Australia (Pereira, Herrmann, Timpson) School of Clinical Medicine, Faculty of Medicine and Health, University of New South Wales (UNSW), Kensington, Sydney, NSW, Australia (Finnie) School of Medicine, Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, SA, Australia (Bhuva) The University of Queensland, Brisbane, QLD, Australia (Franklin, Schmidt) Institute of Innate Immunity, Medical Faculty, University of Bonn, Bonn, Germany |
Issue Date: | 12-Apr-2026 | Copyright year: | 2026 | Publisher: | Nature Research | Place of publication: | United Kingdom | Publication information: | Nature Communications. 17(1) (no pagination), 2026. Article Number: 2477. Date of Publication: 01 Dec 2026. | Journal: | Nature Communications | Abstract: | Pancreatic ductal adenocarcinoma (PDAC) is driven by genetic alterations in the pancreatic epithelium (e.g., KRAS) coupled with dysregulated innate immunity that triggers tumor-promoting chronic inflammation. However, the identity of innate immune molecular regulators as therapeutic targets in PDAC is ill-defined. Here, we show in PDAC patients that elevated tumoral expression of the inflammasome adaptor protein ASC and its downstream effector Caspase-1 is primarily colocalized to the pancreatic ductal epithelium and prognostic for poor survival. In the mutant Kras-driven KPC PDAC mouse model, global and conditional (pancreatic epithelial) ablation of ASC, or nanobody-mediated targeting of extracellular ASC, suppresses pancreatic tumorigenesis. Whole transcriptome profiling and multiplex immunofluorescence reveal that the tumor-promoting activities of epithelial-derived ASC align with molecular pathways for mitochondrial respiration, metabolism (glycolysis), and immune responses. Our discovery that ASC-containing inflammasomes promote PDAC by acting as a molecular bridge between innate immunity, mitochondrial dysfunction and metabolic reprogramming provides the rationale to therapeutically target ASC in cancers.Copyright © The Author(s) 2026. | DOI: | https://dx.doi.org/10.1038/s41467-026-69398-w | PubMed URL: | 41654528 | URI: | https://repository.monashhealth.org/monashhealthjspui/handle/1/58039 | Type: | Article |
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